Review
Interpreting endocrine disruption from an integrative biology perspective

https://doi.org/10.1016/j.mce.2009.02.020Get rights and content

Abstract

The ability of reductionism to advance our understanding of complex biological phenomena is limited. The ecological developmental biology (eco-devo) movement rejects the notion that development is merely the unfolding of a genetic program. Fetal exposure to environmental endocrine disruptors may contribute to the increased incidence of male genital tract malformations, decreased sperm quality, several neoplasms, and altered body weight. Here we discuss problems hindering the study of endocrine disruption (reductionist stance, technically driven research biases, and study of single end points, chemicals and exposure periods). We propose the study of both upward and downward causation and a Systems Biology approach to develop quantitative mathematical models for use in computer simulations that would generate testable predictions. This integrative approach will allow the simultaneous consideration of organismal (systemic) effects and effects on various organ systems. It will promote the identification of similar and unique effects of different endocrine disruptors, and their inter-relationships.

Introduction

At the beginning of the 21st century, we are experiencing a paradigm change in biology. The dominant view during the last fifty years has considered development to be a function of the unfolding of a genetic program where the environment plays virtually no relevant role. This view has prevailed despite studies from the late 19th century illustrating the phenomenon of environmentally triggered polyphenisms. The arbitrary choice of model organisms which thrive in laboratory facilities where the environment is practically invariable, and the dominance of a genocentric view led to developmental genetics, “a discipline that explicitly treated phenotype as a direct ‘readout’ of the nuclear genome” (Gilbert, 2005). This is a misconception that needs to be corrected.

Thanks to the incorporation of new data, prominent among them epidemiological studies highlighting the developmental plasticity of the human fetus, this rigid view of development is now rapidly being replaced (Barker and Hanson, 2004). Several pathways have been identified that could incorporate environmental cues into the building of a phenotype during early development, namely, (i) the neuroendocrine route, whereby the nervous system monitors the environment and transfers signals to the endocrine system, (ii) the epigenetic route, whereby environmental agents change the methylation pattern of genes, thereby altering their transcriptional capabilities, and (iii) the direct modulation of gene expression, particularly by hormonally-active agents (Gilbert, 2005).

This new emphasis on the role of the environment in development has resulted in the creation of a new discipline, ecological developmental biology (eco-devo) and has prompted scientists to hypothesize that fetal exposure to environmental agents, particularly those with hormonal activity, may cause health effects that manifest during adult life. One of these chemicals, the pesticide DDT, was found to be estrogenic in 1950 (Burlington and Lindeman, 1950). The specter of cancer and other adverse health effects in humans, rather than the protection of wildlife or the environment, motivated the US government to ban the agricultural use of DDT in 1973. The normalization of eggshell development in the bald eagle population after DDT was banned allowed evidence of other widespread effects of DDT exposure to be observed. Hatchling birds showed a diversity of developmental malformations (National Research Council, 1999). These developmental malformations were well documented in the Great Lakes area and they were also observed in other ecosystems (Johnson et al., 1993).

In 1991, the Wingspread Conference held in Wisconsin addressed these new data. The participants proposed that the developmental alterations observed in several wildlife species was due to exposure to multiple chemicals that, through different modes of action, disrupted the endocrine system of developing organisms. They noticed that some of the effects observed in the genital tract of wildlife were comparable to those seen in the daughters and sons of women who had been exposed during pregnancy to a synthetic estrogen, diethylstilbestrol (DES), between the years 1948 and 1971 (Herbst and Bern, 1988, Mittendorf, 1995). They postulated that the DES syndrome was an extreme expression of the plasticity of the fetus to environmental cues provided by hormonally active chemicals such as DDT and polychlorinated biphenyls. They also noticed that in addition to the already banned chemicals, other hormonally active chemicals were present in the environment. The anti-oxidant nonylphenol, which had just been shown to leach from laboratory plasticware (Soto et al., 1991), was one such example. Nonylphenol headed a growing list of chemicals that were subsequently identified as endocrine disruptors including plasticizers, disinfectants, sunscreens, and new pesticides (Colborn et al., 1993, Krishnan et al., 1993, Soto et al., 1994, Schlumpf et al., 2004). The participants of the Wingspread Conference concluded that the developmental abnormalities observed initially and predominantly in birds might foreshadow similar problems beginning to be observed in mammals, including humans (Colborn and Clement, 1992). A year later, a meta-analysis concluded that the quantity and quality of human sperm had decreased during the last half-century, coincidentally with the introduction of chemicals into the environment (Carlsen et al., 1992).

The consequences of the DES iatrogenic mishap, as well as the gross developmental anomalies observed in wildlife, were the result of exposure to high doses of hormonally active agents. Ecological developmental biology, which considers the environment a main determinant in the construction of the phenotype, provided the conceptual framework to suspect that the phenotype can be affected by small variations in the endocrine milieu of the developing embryo. In fact, even physiological variation of the hormone levels to which fetuses are exposed results in effects that are manifested during adult life. For example, contiguity to male fetuses in the uterus affects the adult behavior, body weight, reproductive senescence (Clemens et al., 1978, Gandelman et al., 1977, vom Saal, 1989, vom Saal et al., 1992) and the development of the fetal mammary gland in females (Vandenberg et al., 2007). This perspective was a key component in the development of the Wingspread Statement.

Increasing concern about environmental hormones as causal agents of human disease soon started to appear in the literature, resulting in the formulation of the endocrine disruptor hypothesis. This hypothesis states that the increased incidence of malformations of the male genital tract, several neoplasms (uterine leiomyoma, testicular cancer and breast cancer), and the decreased sperm quality observed in European and US populations over the last fifty years was due to fetal exposure to endocrine disruptors (Markey et al., 2003, Skakkebaek et al., 1998). Laboratory animal research and epidemiological studies produced a body of evidence supporting the credibility of this hypothesis. Subsequent research by developmental biologists aimed at testing the endocrine disruptor hypothesis revealed that developmental exposure to these agents produced additional effects to those alluded to above, such as obesity. Based on the correlation between industrial chemical use and increased body weight in industrialized countries, Baillie-Hamilton proposed that the rapid rise in obesity might also be related to the rising levels of industrial chemicals in the environment (Baillie-Hamilton, 2002).

One particularly well studied endocrine disruptor is the ubiquitous contaminant bisphenol-A (BPA), a component of plastics and epoxy resins. BPA has structural similarities to DES, and like DES, it is a xenoestrogen. We have chosen BPA as a model for this commentary because the multiple deleterious effects of this chemical in experimental animals resemble recent trends observed in humans. In fact, these similarities prompted the National Institutes of Environmental Health Sciences (NIEHS) to call a group of experts to evaluate the evidence; their findings were published in a series of articles and were summarized in the Chapel Hill Consensus Statement. There they stated that “the wide range of adverse effects of low doses of BPA in laboratory animals exposed both during development and in adulthood is a great cause for concern with regard to the potential for similar adverse effects in humans. Specific examples include the increase in prostate and breast cancer, uro-genital abnormalities in male babies, a decline in semen quality in men, early onset of puberty in girls, metabolic disorders including insulin resistant (type 2) diabetes and obesity, and neurobehavioral problems such as attention deficit hyperactivity disorder (ADHD)” (vom Saal et al., 2007).

Section snippets

Carcinogenesis in the womb: a challenge to the Somatic Mutation Theory

According to the somatic mutation theory, cancer is caused by mutations in the DNA of a single cell (Hahn and Weinberg, 2002). The research emanating from this theory has not provided either an explanation of cancer pathogenesis, reliable tools for cancer prevention, or successful therapies for most cancers. Due to these shortcomings, an old notion that originated in the late 19th century when pathologists described the histological pattern of tumors has resurfaced. It suggested that altered

Endocrine disruption challenges “science as usual”

The multiple effects observed long after cessation of perinatal BPA exposure contradicts traditional reasoning, in which an estrogenic compound like BPA is expected to cause alterations in estrogen target tissues only. These findings merit a detour into epistemology, the science of “how do we know what we know”, which becomes relevant to biologists seeking explanations for the phenomena being observed. There are at least two different types of explanations for reproducible observations: in

How do we overcome the limitations of Reductionism? Consider organicism, the study of emergent phenomena

The complexity of multicellular organisms generates the perception of a discontinuity between low and high level phenomena. For instance, to know how a joint works, we have to understand the mechanics of movement and shock absorption. We cannot deduce it solely from the molecular components of hyaline cartilage. Thus, properties at one level of biological complexity (for instance, tissues) cannot be ascribed directly to their component parts (cells, extracellular matrix); they arise only

Acknowledgements

This work was supported by NIH grants ES0150182, ES012301 and ES08314. We are grateful to Cheryl Schaeberle and Michael Askenase for their technical and editorial assistance.

References (60)

  • C. Sonnenschein et al.

    Theories of carcinogenesis: an emerging perspective

    Semin. Cancer Biol.

    (2008)
  • F.S. vom Saal et al.

    Chapel Hill bisphenol A expert panel consensus statement: Integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure

    Reproductive Toxicol.

    (2007)
  • P. Alonso-Magdalena et al.

    The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance

    Environ. Health Perspect.

    (2006)
  • P.F. Baillie-Hamilton

    Chemical toxins: a hypothesis to explain the global obesity epidemic

    J. Altern. Complem. Med.

    (2002)
  • M.H. Barcellos-Hoff et al.

    Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells

    Cancer Res.

    (2000)
  • D.J.P. Barker et al.

    Altered regional blood flow in the fetus: the origins of cardiovascular disease?

    Acta Paediatricia

    (2004)
  • H. Burlington et al.

    The effect of DDT on testes and secondary sex characters of white leghorn cockerels

    Proc. Soc. Exp. Biol. Med.

    (1950)
  • E. Carlsen et al.

    Evidence for the decreasing quality of semen during the past 50 years

    Br. Med. J.

    (1992)
  • C.R. Cederroth et al.

    A phytoestrogen-rich diet increases energy expenditure and decreases adiposity in mice

    Environ. Health Perspect.

    (2007)
  • T. Colborn et al.

    Developmental effects of endocrine-disrupting chemicals in wildlife and humans

    Environ. Health Perspect.

    (1993)
  • Wingspread consensus statement. In: Colborn, T., Clement, C. (Eds.), Chemical Induced Alterations in Sexual and...
  • S.E. Fenton et al.

    Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7 8-tetrachlorodibenzo-p-dioxin (TCDD)

    Toxicol. Sci.

    (2002)
  • R. Gandelman et al.

    Contiguity to male foetuses affects morphology and behaviour of female mice

    Nature

    (1977)
  • S.F. Gilbert

    Mechanisms for the environmental regulation of gene expression: ecological aspects of animal development

    J. Biosci.

    (2005)
  • S.F. Gilbert et al.

    Embracing complexity: organicism for the 21st century

    Dev. Dyn.

    (2000)
  • F. Grun et al.

    Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates

    Mol. Endocrinol.

    (2006)
  • F. Grun et al.

    Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling

    Endocrinology

    (2006)
  • W.C. Hahn et al.

    Modelling the molecular circuitry of cancer

    Nat. Rev. Cancer

    (2002)
  • Herbst, A.L., Bern, H.A., 1988. Developmental effects of diethylstilbestrol (des) in pregnancy. Thieme-Stratton: New...
  • S.-M. Ho et al.

    Developmental exposure to estradiol and bisphenol a increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4

    Cancer Res.

    (2006)
  • Cited by (23)

    • Morphometric signatures of exposure to endocrine disrupting chemicals in zebrafish eleutheroembryos

      2019, Aquatic Toxicology
      Citation Excerpt :

      The disruption of the steroidogenic pathway by EDCs is well-known and has been widely reported (Benninghoff et al., 2011; Carpenter, 2013; Lyssimachou et al., 2006; McGinnis and Crivello, 2011; Sanderson, 2006; Shi et al., 2008; Vandenberg et al., 2009). However, it has been shown that EDCs disrupt other hormonal pathways, pointing out the need of more complex and integrative interpretations (Martínez et al., 2018; Regnier and Sargis, 2014; Soto et al., 2009; Vandenberg et al., 2009). In the past, the study of EDCs has focused on lethality, effects at the phenotype level and/or identification and measurement of biomarkers of exposure (Kashiwada et al., 2002; Kinch et al., 2016; Scholz and Mayer, 2008).

    • Screening of bisphenol A, triclosan and paraben analogues as modulators of the glucocorticoid and androgen receptor activities

      2015, Toxicology in Vitro
      Citation Excerpt :

      The Registration, Evaluation, and Authorization of Chemicals (REACH) program reported about 140,000 substances that were pre-registered by 1 December 2008 in the European Union (Judson et al., 2009). Several of these chemicals can interfere with functions of the endocrine system (Soto et al., 2009). Such endocrine disrupting compounds (EDCs) were defined by the U.S. EPA as “exogenous agents that interfere with the production, release, transport, metabolism, binding, action, or elimination of the natural hormones in the body responsible for the maintenance of homeostasis and the regulation of developmental processes”.

    • Environmentally induced epigenetic transgenerational inheritance of phenotype and disease

      2012, Molecular and Cellular Endocrinology
      Citation Excerpt :

      In spite of the concept that a true understanding of how organisms operate arises only when taking this integrative approach, the recent history of biology has been mainly written from a reductionist perspective. The genetic reductionism of the past years has left many gaps of knowledge, which are mainly due to the absence of a consideration of emergent properties (Soto et al., 2009). Emergent properties will only be adequately interrogated when organism systems as a whole and not only as a collection of components are included as the focus of research (Cornish-Bowden et al., 2004).

    View all citing articles on Scopus
    View full text